Aryl-substituted psperidylpropanols



United States e .ifiilii phenyllithium are obtained by condensation of ethyliithium with p-bromochlorobenzene and p-dibromobenzene 2,833,776 respectively [see Izvestiya Altademii Nauk SSSR, Otdeleni ARYLSUBSTITUTED PIPERIDYLPROPANOLS' Khimicheskikh Nauk 126-134 (1953); C. A. 48, 3285 r 1954)].

Arlo Wayne Ruddy, Morris Plains, N. J., assignor to In cases where the phenyl substituent R or R of Warner-Lambert Pharmaceutical Company, New York, Formula VIII is required to he the hydroxyl radical, the e 'p Delaware preferred preparative procedure comprises temporarily protecting the phenolic function of the precursors of No Drawmg' gg i afgg ggf 1955 10 compounds V and VII prior to preparation of the cor- I responding organometallic compound. Such temporary 6 Claims. protection may be obtained for example by condensing the appropriate halophenol with benzyl chloride fol- I lowed by reaction of the resulting benzylhalophenyl This invention relates to new compounds of pharmaether with magnesium or lithium. After the resulting ceutical value, particularly as antispasmodics. v organometallic intermediate is condensed with the ap- In accordance with my invention there are provided propriate piperidylpropionie ester or piperidylpropiocompounds having the general structural formula: phenone derivative, the substituted diphenylcarbinol ultimately obtained is hydrogenated in the presence of a palladium catalyst in order to remove the protective ;benzyl group, thereby regenerating the free phenolic R OCHICH1C hydroxyl function and yielding the desired compound OH 6 VIII.

The free bases of my invention are water-insoluble erein R denotes lower alkyl; and R and R which substances. Water-soluble salts may be formed by treatmay be the same or different, denote hydroge h log 1: ing the free bases with acids such as hydrochloric acid, hydroxyl, methoxyl or methyl. These compounds have hydrobromic acid, sulfuric acid, tartaric acid, citric acid been found to possess highly eifeetive antispasmodic acsuccinic acid, With Suitablfi Organic halides, -a tivity. alkyl halides such as methyl chloride or methyl bromide The compounds of my invention may be prepared in or other organic halides such as thienylmethyl chloride. accordance with the following scheme: Among the compounds which may be prepared in Quaternlzation esterificatiun with R Br N\ CHzCHrCOOH N\ CH2CH:C OOAJK I II condensation with catalytic M@ hydrogenation R N CHzCHzC O OAlK R -N OHiCHaC O O-AIK Br- III IV v condensation 32 with Ra R2 M'@ R1N anionic n O 0% 3 0 VI VII VIII wherein R R and R are as defined above, AlK denotes accordance with this invention are the following: lower alkyl, and M and M denote lithium or the mono 3 N eth 1 4 i erid yl)-1,l-d1 henyl-l ropanol valent radical MgBr. In cases where R specifically .515. Z g 5 p denotes methyl, the compounds of I'ormula IV may be 3 (N methy1 4 piperidy1) 1,P anisy1 1 pheny1 Lpropanol obtained from the compounds of Formula II directly dy1) 1,1 di(p am.syl) l pmpanol by catalytic hydrogenation m the presence of formalde- 3 (N methyl 4 piperidyl) 1 (pchlorophgnyly hyde, as Well as by the route represented in the above pheny1 1 pr OP an 01 scheme. In cases where R and R are the same, the 51: methyl 4 piperidyl) 1,1 (mp chloro compounds of Formula VIII may be obtained from the compounds of Formula IV directly by condensation with P ,Y :,;f f 1 p hydroxyphenylan excess of the organometallic compounds V. On the 1 pheny1 1 pmpano1 other hand if R and R are diiferent, a limited amount 3 (N methyl 4 piperidyl) 1 1 di p hydroxy of the organometallic compound is condensed with the phenyl) l pmpanol compounds of Formula IV to furnish the intermediate 3 1 p1per1 y 1,1 d1(p tolyl) l propanol ketones of Formula VI WhlCh are then converted to the 3 (N methyl 4 piperidyl) 1 pheny1 1 (p t01yn 1 pmpano1 corresponding carbmols of Formula VIII as indicated 3 (N ethyl 4 piperidy1) l,l di(o tolyl) 1 Dr0pano1 in the above scheme.

The organometallic compounds V d V11 may b as Well as acid addition salts thereof and quaternary salts readily obtained from the corresponding halobenzenes thereofin accordance with prior art procedures. Thus phenyl- Example p (4 pyridyl) pmpionate magnesium bromide and phenyllithium may be obtained directly from bromobenzene;p-methoxyphenylmagnesium To a suspension of 119 g. of p-(4-pyridyD-prop1onic bromide and p-methoxyphenyllithium are derived from acid (W. F. Doering, and R. A. N. Weil, I. Am. Chem. p-bromoanisole; p-chlorophenyllithium and p-bromo- Soc. 69, 2465 (1947)), in 350 ml. of absolute ethanol was Example 2. Ethyl [3-(N-methyll-piperidyl)prpi0nale This ester can be prepared by either of the two following procedures:

Procedure A.-A solution of 35.8 g. (0.2 mole) of ethyl B-(4-pyridyD-propionate in absolute ethanol-glacial acetic acid (1:1) was reduced at 45 lbs. of hydrogen and room temperature using platinum oxide catalyst. About 50 hours were required. to completely saturate the pyridine ring. To the mixture containing the 4'piperidyl ester was added 17 ml. of 37% aqueous formaldehyde and the hydrogenation continued. The N-methylation was complete in about 90 minutes at 45 lbs. of hydrogen and room temperature. The catalyst was filtered out and the filtrate made acid to pH 3 with cone. hydrochloric acid. The solution was evaporated to a. heavy syrup under reduced pressure and the base was liberated using 50 g. of potassium carbonate and cc. of water. The base was extracted with chloroform by decantation and the extract dried over anhydrous potassium carbonate. The solvent was removed and the residue was fractionated under reduced pressure. An 85% yield (34.6 g.) of ethyl fl-(N-methyl-4-piperidyl)-propionate was obtained; B. P. 1'19l22/10 mmg, 1.4530.

Procedure B.-A solution of 35.8 g. (0.2 mole) of ethyl fi-(4-pyridyD-propionate in 40 ml. of methanol was heated to 50 C. and methyl bromide passed in until the quaternization was complete and the solution no longer basic. The reaction was refluxed to remove the excess methyl bromide and then the methanol removed on a steam bath under reduced pressure. Ether was added and the residue was induced to crystallize. The quaternary salt was filtered, washed with ether and dried. A practically quantitative yield of product was obtained; M. l. 99100C. The methobromide was then dissolved in 350 ml. absolute ethanol and reduced at 45 lbs of hydrogen and 50 C. with platinum oxide catalyst. The reduction was complete in 2 to 3 hours. The catalyst was removed and the solvent distilled in vacuum. The residue was made strongly basic with 50% sodium hydroxide, extracted with ether, and the extracts dried over anhydrous potassium carbonate. The solvent was removed and the product fractionated under reduced pressure. An 81% yield of ethyl fi-(N-methyl-4-piperidyl)-proponate was obtained; B. P. 8081/1.2 mm; n 1.4547.

Example 3 .--3-(N-merhyl-4-piperidyl )-J ,1 -diphenyl- J-propanol Thiscompound can be prepared by either of the two following procedures:

Procedure A.-A solution of phenylmagnesium bromide was prepared in the usual manner from 10.5 g. (0.435' mole) magnesium turnings and 68.3 g. (0.435 mole) bromobenzene in 250 ml. dry ether. The solution was then cooled in an ice bath and a solution of 34.6 g. (0.17 mole) of ethyl B-(N'methyl-4-piperidyl)-propionate in 200 ml. dry benzene was added slowly with stirring. The mixture was allowed to warm up slowly and then was refluxed for two hours. The reaction was hydrolyzed by pouring into ammonium chloride solution. The organic layer was separated, washed with water then 5% sodium hydroxide solution, and again with water. After drying over anhydrous potassium carbonate the ether and benzene were removed under reduced pressure. The residue was induced to crystallize by stirring with Skellysolve C. There was obtained 7.4 g. of 3-(Nmethyl-4-'piperi- 4 dyl)-1,1-dipheny1-1-propanol base; M. P. -146 C. By distilling the mother liquor 17.6 g. of w-(N-methyl-4-piperidyl)-propionphenone, B. P. -190/l0 mm., n 1.5351, was recovered. This ketone was formed by the addition of only one mole of pheuylmagnesium bromide to the ester. The ketone is readily converted to the de-.

sired product by the addition of one mole of phenyl lithiumin the usual manner.

Procedure B.--A solution of phenyl lithium was prepared by adding 343 g. (2.8 moles) of bromobenzene in 750 ml. of dry ether to a stirred suspension of 30.3 g. (4.37 moles) of lithium ribbon in 1250 ml. of dry ether.

After the reaction was complete it was chilled to about 0 C., and 145 g. (0.728 mole) of ethyl fl-(N-methyl-4- piperidyl)-propionate in 1 liter of dry benzene was added with stirring. During the addition the temperature was held at about 5 C. or below. The reaction mixture was then gradually warmed and finally refluxed for six hours. It was hydrolyzed by pouring into a cold solution of ammonium chloride and then extracted with chloroform. The combined extracts were dried over anhydrous potassium carbonate and the solvent was removed under reduced pressure. The residue was recrystallized from absolute ethanol and 157 g. (69.6%) of the desired 3-(N-methyl-4-piperidyl)-1,l-diphenyl-lpropanol base, M. P. l46l47 C., was obtained.

Example 4.3-(N-methyl-4-piperidyl)-I,1-diphenyl-1- propmtol hydrochloride The base described in the preceding example was dissolved in anhydrous ether and precipitated with hydrogen chloride. The salt when recrystallized from ethanol was a colorless, crystalline solid melting at 207.5208.5 C.

Example 5.-3-(N-rr ethyl-4-piperidyl)-1,1-cliphenyl-1- propanol methobromide Example 6. Ethyl 3- (N-eihyl-l-piperidyl)-pr0pionate When 49 g. of ethyl fi-(4-pyridyl)-propionate ethobromide was reduced and purified. under the conditions described in Example 2B, the desired ester was obtained in 77% yield, B. P. 9294 C./l.4 mm, 11 1.4606. The hydrobromide salt of the ester melted at 118-119 C.

Example 7.-3-(N-ethyl 4 pipcridyl) 1,1 diphenyl-I- propanol hydrochloride To an ether solution of phenyl lithium, prepared from 50.4 g. of bromobenzene and 4.46 g. of lithium ribbon,

'was added 22.9 g. (0.017 mole) of ethyl fi-(N-ethyl-4- piperidyl)-propionate. The conditions of the reaction and the work up were those described in Example 3B. The 3-(N-ethyl-4-piperidyl)-l,l-diphenyl-l-propanol base when recrystallized from Skellysolve B melted at 101- 103" C- The corresponding hydrochloride when recrystallized from ethanol and ether melted at 199-201 C.

Example 8.3-(N-ethyl 4 piperidyl) 1,1 diphenylJ- propanol methobromide Procedure A.-Wh'en the base from Example 7 was quaternized with methyl bromide in methanol the correspending methobromide was produced, M. P. 262-264 C'., with decomposition. i

Procedure B.--When the 3-(N-methyl 4 piperidyU- 1,"l-diphenyl-l-propanol base from Example 3 was quater nized with ethyl bromide by refluxing in methanol the identical compound was produced as described in Example 8A, MQP. 263264, with decomposition.

Other compounds coming within the scope of this invention may be manufactured by following the procedures set forth above, using equivalent amounts of appropriate reactants. For example, the di- (p-chlorophenyl) analog of the product of Example 3 may he prepared by employing equivalent amounts of p-chlorophenylmagnesium bromide '01 p-chlorophenyl lithium in place of the phenylmagnesium bromide or phenyl lithium employed in procedures A and B of Example 3.

I claim:

1. A compound selected from the group consisting of compounds having the formula:

wherein R is lower alkyl; R is selected from the group consisting of hydrogen, halogen, hydroxyl, methoxyl, methyl; R is selected from the group consisting of hydrogen, halogen, hydroxyl, methoxyl, methyl; and salts thereof.

2. 3-(N-methyl-4-piperidyl)-1,1-dipheny1-1-propanol.

3. 3-(N-methyl-4-piperidyl) 1,1 diphenyl-l-propanol hydrochloride.

4. 3-(N-methyl-4-piperidyl) 1,1 diphenyl-l-propanol methobromide.

5. 3-(N-methyl-4-piperidyl) 1,1 di(p anisyl)-1-propanol. 1

6. 3-(N-methyl-4piperidyl) 1 (p chlorophenyl)-1 phenyl-l-propanol.

References Cited in the file of this patent UNITED STATES PATENTS 2,682,543 Adamson June 29, 1954 2,739,968 Sperber Mar. 27, 1956 FOREIGN PATENTS 503,775 Belgium June 30, 1951 507,597 Belgium Dec. 31, 1951 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 